Phospholipid derivatives containing higher elements of the fifth main group

ABSTRACT

Phospholipid derivatives containing higher elements of the Vth main group (P, As, Sb, Bi), their method of preparation and antineoplastic and antimicrobially active medications that can be prepared from the phospholipid derivatives.

This is a Continuation-in-Part of: National Appln. No. 08/421,920 filedApr. 14, 1995 now U.S. Pat. No. 5,637,577 which is a Division of Ser.No. 08/124,492, filed on Sep. 22, 1993, now U.S. Pat. No. 5,449,798.

The present invention relates to novel compounds which may be used intumor therapy and for the treatment of skin and auto-immune diseases.

BACKGROUND OF THE INVENTION

Long-chain alkylphosphocholines with an antimicrobial action aredescribed by Kanetani et al., Nippon Kayaku Kaishi, 9, 1452 (1984).

European patent application 108 565 (applicant: Takeda) relates tocompounds of the general formula ##STR1## in which R¹ is an aliphatichydrocarbon radical with 8-30 carbon atoms,

the radicals R², R³ and R⁴ are the same or different or hydrogen orlower alkyl radicals or where the group NR² R³ R⁴ represents a cyclicammonium group and n has the value 0 or 1. These compounds are stated tohave an anti-tumour effect and a fungus-inhibiting effect.

SUMMARY OF THE INVENTION

The compounds of the invention may be used in tumour therapy and for thetreatment of skin and auto-immune diseases, in particular the compoundsof Formula I, ##STR2## where R⁵ represents a straight-chain or branchedalkyl radical with 10-24 carbon atoms which may also contain one tothree double or triple bonds,

A represents a simple bond or one of the groups with the formulae II-VI##STR3## where R⁷ represents a straight chain alkyl group with 1 to 4carbon atoms which may also be branched.

The groups (II) to (VI) are so oriented that the oxygen atom is bound tothe phosphorus atom of the compound of formula I.

X=oxygen or sulfur atom or NH,

when A=single bond

X=oxygen or sulphur atom when A is a compound of the groups of formulae(II) to (VI)

A₁ =straight-chain or branched alkyl radical with 2 to 10 carbon atomswhich may also be unsaturated and be substituted by halogen or hydroxygroups.

R⁶ =.sup.(+) YR⁸ R⁹ R¹⁰ with R⁸ -R¹⁰ =straight chain, branched or cyclicalkyl radicals with 1 to 6 carbon atoms, which may be the same ordifferent, or hydrogen

Y=P, As, Sb or Bi, or a group of formula VII ##STR4## with n=0 or 1W=CH₂, O, NH or S; provided n=1, if W is not equal to CH₂,

where Y has the meanings P, As and Sb.

The compounds of formula I with Y=As and Sb are for example suitable forthe treatment of protozoal diseases. All compounds are, moreover,particularly suitable as agents against tumor diseases.

The compounds of the invention are suitable for the treatment of blooddisorders, such as of anemias as can occur in combination with tumordiseases. In addition, the compounds of the invention may be used forthe treatment of diseases of the bone system, for example osteoporosis.

In addition, the compounds of Formula I may be used for the treatment ofvirus disorders and bacterial infections.

The compounds are characterised by low toxicity.

The compound according to Example 3 thus has an LD₅₀ on singleadministration per os in the mouse of more than 1470 mg/kg body weight.

The following tumors are treatable using the compounds of the invention:

Solid tumors can be treated in general, particularly:

mamma carcinoma

head-neck carcinoma

colon carcinoma

prostate carcinoma

The treating can be a long term treatment with a low daily dosage of5-100 mg/kg per body weight. On the other hand, a cyclic treatment canbe used with dosages of 100-500 mg/kg per body weight that may beadministered for example in form of 3 dosages a day.

Preparation

The following are procedures for the preparation of the compounds of theinvention.

Process 1

The first step of the single pot process consists in the reaction ofphosphorus oxychloride with alcohol, thioalcohol or amine in halogenatedhydrocarbons, saturated cyclic ethers, acyclic ethers, saturatedhydrocarbons with 5 to 10 carbon atoms, liquid aromatic hydrocarbonswhich may also be substituted by halogen (in particular chlorine) or inmixtures of the above mentioned solvents or without solvents, optionallyin the presence of a conventional base substance. Halogenatedhydrocarbons that may for example be considered are hydrocarbons with 1to 6 carbon atoms, where one or several or all hydrogen atoms arereplaced by chlorine atoms. Methylene chloride, chloroform, ethylenechloride, chlorobenzene, dichlorobenzene may for example be used. Ifhalogen-substituted aromatic hydrocarbons are used, these are preferablysubstituted by one or two halogen atoms.

Saturated cyclic ethers that may for example be used are ethers with aring size of 5-6 which consist of carbon atoms and one or two oxygenatoms.

Examples thereof are tetrahydrofuran, dioxane.

The acyclic ethers consist of 2 to 8 carbon atoms and are liquid. Thefollowing may for example be used: diethyl ether, diisobutyl ether,methyl-tert.-butyl ether, diisopropyl ether.

Saturated hydrocarbons that may be used are unbranched and branchedhydrocarbons that consist of 5 to 10 carbon atoms and are liquid.Examples are pentane, hexane, heptane, cyclohexane.

Aromatic hydrocarbons that may for example be considered are benzene andalkyl-substituted benzenes, the alkyl substituents containing 1 to 5carbon atoms.

Base substances that may be considered both for the reaction of thephosphorus oxychloride with the alcohol, thioalcohol or amine and alsofor the subsequent reaction with the phosphonium, stibonium orbismuthonium salt are amines, for example aliphatic amines of theformula NR⁷ R⁸ R⁹, where R⁷, R⁸ and R⁹ are the same or different andrepresent hydrogen or C₁ -C₆ =alkyl or also aromatic amines such aspyridine or picoline. Furthermore it is also possible to use quinoline,diisopropylamine, isoquinoline, triethylrmine, Hunigs Base (Hunig,Kissel, Chem. Ber., 91 (380) 1958).

During the reaction with the phosphonium, stibonium or bismuthonium saltthe base substance required for this purpose may be added at the sametime or also before the phosphonium, stibonium or bismuthonium salt. Asolvent is required for this reaction in any event; this means that ifthe first step of the reaction occurs without a special > solvent, asolvent has to be added at this stage.

The Mol ratio of phosphorus oxychloride to alcohol, thioalcohol or amineis for example between 1.5:1 and 0.8:1.

If the reaction of the phosphorus oxychloride with the alkanol orthioalkanol or the amine occurs in the presence of a base substance, theamount of base substance is for example 1 to 3 mol for each Mol POCl₃.

For the subsequent reaction with the phosphonium, stibonium orbismuthonium salt, the amount of base substance used is for example 1 to5 Mol for each Mol of alcohol, thioalcohol or amine.

The reaction temperature of the reaction of phosphorus oxychloride withalcohol, thioalcohol or amine with the amine is between -30° C. and +30°C., preferably -15° C. and 0° C., in particular -10° C. and 0° C. Thereaction time of this reaction is for example 0.5-5 hours, preferably1-3 hours, in particular 1.5-2 hours. If the reaction occurs in thepresence of a base, it generally occurs quickly (about 30 minutes).

The product obtained is reacted, without isolation and purification, inan inert solvent with a phosphonium, arsonium, stibonium or bismuthoniumsalt of Formula VIII

    OH--A.sub.1 --R.sup.6                                      Formula VIII

wherein A₁ and R⁶ have the meanings given above.

Arsenocholine and its salts can for example be prepared according to theinstructions set out in K. Irgolic, Applied Organometallic Chemistry(1987) 1, p. 403-412.

The phosphonium, stibonium or bismuthonium salt is added thereafter inportions or all at once.

In accordance therewith, salts with mineral acids (such as sulphuricacid, hydrochloric acid) as well as salts with organic acids such asacetic acid, para-toluenesulfonic acid and the like may be used as saltsof the phosphonium, stibonium or bismuthonium salt.

This reaction step occurs in an inert solvent. The solvents that may beconsidered for this step are the same as those used for the reaction ofphosphorus oxychloride with alcohol, thioalcohol or amine if thisreaction occurs in a solvent.

The base substance is then dissolved in one of the solvents mentioned,or added dropwise without solvent.

The solvents used for the base substance in this case are preferably:halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers,saturated hydrocarbons with 5 to 10 carbon atoms, liquid aromatichydrocarbons or mixtures of the above mentioned solvents.

These are the same solvents as can be used for reacting phosphorusoxychloride with alcohol, thioalcohol or amine.

Addition of the base substance increases the temperature. Care is takento ensure that the temperature is maintained within a range between 0°C. to 40° C., preferably 10° C. to 30° C., in particular 15° C. to 20°C.

The reaction mixture is then stirred at 5° C. to 30° C., preferably 15°C. to 25° C., (for example for 1 hour to 40 hours, preferably 3 hours to15 hours).

The reaction batch is hydrolyzed by adding water, during which thetemperature should be maintained between 10° C. and 30° C., preferably15° C. and 30° C., in particular between 15° C. and 20° C.

The previously mentioned hydrolysis liquids can also contain basesubstances. Base substances of this type that may be considered arecarbonates and hydrogen carbonates of alkali and alkaline earth metals.

To complete the hydrolysis, stirring is then continued for a further 0.5hours to 4 hours, preferably 1 to 3 hours, in particular 1.5 to 2.5hours at 10° C. to 30° C., preferably at 15° C. to 25° C., in particularat 18° C. to 22° C.

The reaction solution is then washed with a mixture of water andalcohols (preferably aliphatic saturated alcohols with 1 to 4 carbonatoms), which may optionally still contain a base.

The mixing ratio water:alcohol can for example be between 5 and 0.5,preferably 1-3 (V/V).

Bases which may for example be considered for the washing liquid arecarbonates and hydrogen carbonates of alkali and alkaline earth metalsas well as ammonia (for example aqueous ammonia). A 3% sodium carbonatesolution in water is particularly preferred.

The reaction solution may then optionally be washed with an acidsolution.

The acid washing is advantageous for removing unreacted base portions ofthe reaction solution, particularly when methylene chloride is used assolvent.

The washing solution consists of a mixture of water and alcohols.Mixtures of aliphatically saturated alcohols with 1 to 4 carbon atomsmay preferably be considered. Optionally it is possible for an acidsubstance to be present. The mixing ratio water:alcohol can for examplebe between 5 and 0.5, preferably 1-3 (V/V).

Mineral acids and organic acids may for example be considered as acidsubstance for the washing liquid, for example hydrochloric acid,sulphuric acid or tartaric acid and citric acid. A 10% solution ofhydrochloric acid in water is particularly preferred.

The resulting product is then washed once more with a mixture of waterand alcohols. Mixtures of aliphatic saturated alcohols with 1 to 4carbon atoms may preferably be considered, it optionally also beingpossible for a base substance to be present as well.

The mixing ratio water:alcohol can for example be between 5 and 0.5,preferably 1-3.

The washed phases are then combined and dried in conventional manner,the solvent then being removed (preferably under reduced pressure, forexample 5 to 100 hPascal), optionally after addition of 150-1000 ml,preferably 300-700 ml, in particular 450-550 ml of an aliphatic alcohol(for each Mol part by weight of dry product).

Alcohols that may be considered are preferably saturated aliphaticalcohols with a chain length of 1 and 5 carbon atoms. Particularlypreferred alcohols in this case are n-butanol, isopropanol. This alcoholtreatment is intended to totally remove residual water. The product soobtained can be purified in the conventional manner (for example bychromatography, recrystallisation).

Process 2

consists of the reaction of a cyclic phosphoric acid triester with acompound of formula X or XI.

The cyclic phosphoric acid ester is obtained according to EP 108 565 byreacting the cyclic phosphoric acid diester chloride with the alkanol.

A compound of formula IX ##STR5## where m=2 or 3, is reacted with acompound of formula (X) or (XI) YR⁶ R⁷ R⁸ ##STR6## (other meanings, seeformula I) in an inert solvent at increased temperature.

Inert solvents that may be considered are aliphatic nitrites, forexample acetonitrile, propionitrile, and also polar solvents such asN-methylpyrrolidone, dimethylformamide, dimethylacetamide.

The reaction temperature is between 30° C. and 140° C., preferablybetween 50° C. and 120° C., quite particularly between 70° C. and 100°C.

This reaction may be carried out both at atmospheric pressure and alsoat elevated pressure. The pressure is between 1000 hPa and 2000 hPa,preferably between 1000 hPa AND 1750 HpA and, quite particularlypreferred, between 1000 HpA and 1500 HpA.

The reaction time is between 0.5 hours and 4 hours; if the reaction iscarried out under elevated pressure, the time is for example 2 hours at1500 hPa and 85° C.

Process 3

Reaction of activated derivatives of the phosphoric acid esters

This process consists of the reaction of hydrogen phosphate withcompounds of the General Formula XIII ##STR7##

In formula XIII, R¹ X, A, A₁ and R⁶ have the meanings given earlier.

Z=represents a group according to formulae X or XII.

HO in the formula for the hydrogen phosphate can be replaced by halide,tosylate, mesylate and triflate.

Carbodiimides such as dicyclohexylcarbodiimide may be used asdesiccating agents in the condensation reaction.

Aprotic, polar solvents such as acetonitrile, dimethylformamide,dimethylacetamide, dimethylsulfoxide, N-methyl-pyrrolidone andchlorinated hydrocarbons may be considered as solvents for the variantof the process.

The temperature is for example 20-80° C., 40-60° C. being particularlypreferred. The reaction time is for example 4 hours.

Process 4

A compound of the general formula XII which represents an activatedphosphoric acid ester at the aliphatic radical ##STR8## where Z¹=chlorine, bromine, mesylate (XII), tosylate or iodine (other meaningsas before) is reacted with a compound of formulae (X) or (XI).

This reaction occurs in known manner without solvents or in an inertsolvent at temperatures between 50° C. and 150° C.

The solvents that may be considered are the same as for Process 2.

The reaction is followed by conversion with acid-binding orhalogen-binding substances such as Ag₂ CO₃ and with bases, for examplewith alkali metal carbonates and alkaline earth metal carbonates andorganic amines. Solvents may be aliphatic alcohols, for examplemethanol, ethanol and isopropanol. This step may also be at elevatedtemperature.

The exclusion of moisture and atmospheric oxygen, conventional in themetal organic field, should be observed before all reactions arecompleted.

Purification:

The purification process may follow all 4 processes. The above describedcompound may be purified by dissolving the residue formed afterevaporation of the reaction medium, optionally under reduced pressure inan organic solvent (preferably lower alcohols with a water content of0-4%, such as methanol, ethanol, isopropanol, n-butanol) and treatingwith mixed bed ion exchangers or successively with acid and base ionexchangers. The filtrate obtained is then stirred with a mixed bed ionexchanger, for example Amberlite® MB3, for example for 1 to 5 hours,preferably 2 hours, at 10° C. to 50° C., preferably 20° C. Instead of amixed bed ion exchanger, purification may also be carried outsuccessively with an acid ion exchanger and a base ion exchanger.

All insoluble solids containing ion exchanging groups may be used as ionexchangers.

Acid ion exchangers are those which for example contain acid groups suchas sulfonic acid groups, carboxyl groups. Examples are ion exchangerswith sulfonic acid groups in a polystyrene matrix, such as Amberlite® IR120, Dowex® HCR, Duolite® C 20 or Lewatit® S 100. Weakly acidic ionexchangers are for example those which carry carboxylic acid groups onthe basis of a polyacrylic acid matrix, such as Amberlite® IRC 76,Duolite® C 433 or Relite® CC.

Base ion exchangers that may for example be considered are those havingprimary, secondary, tertiary or quaternary amino groups on a polymermatrix (for example polystyrene matrix), such as Duolite® A 101,Duolite® A 102, Duolite® A 348, Duolite® A 365, Duolite® A 375,Amberlite® IRA 67, Duolite® A 375, Amberlite® IRA 458 and Duolite® A132.

Mixed bed ion exchangers are mixtures of acid and alkaline ion exchangerresins, such as Amberlite® MB1, Amberlite® MB2, Amberlite® MB3 andAmberlite® MB6.

Reference is further made to Ullmann's Encyclopedia of IndustrialChemistry, 5th Edition 1989), Volume A14, p. 450 which describes allcommercially conventional ion exchangers which may be used in thepurification process.

After the removal of the ion exchanger resin, evaporation is effected at40° C. to 70° C. under reduced pressure (for example 20 Torr to 200Torr) and followed by recrystallisation from halogenated hydrocarbons,saturated aliphatic ketones, alcohol/ketone mixtures or from saturatedor aromatic hydrocarbons.

Halogenated hydrocarbons that may be considered for therecrystallisation are for example hydrocarbons with 1 to 6 carbon atoms,one or several or all hydrogen atoms being replaced by chlorine atoms.

Methylene chloride, chloroform, ethylene chloride, chlorobenzene may forexample be used.

The alcohols may be saturated aliphatic alcohols with 1 to 6 carbonatoms and 1 to 3 hydroxyl groups. Ketones may be saturated, aliphaticketones with 3 to 6 carbon atoms.

The mixing ratio alcohol:ketone is 1 to 1-5 (volume/volume).

An ethanol/acetone mixture in the ratio 1:1 (V/V) is particularlypreferred.

Saturated or aromatic hydrocarbons may be considered: high-boiling pointpetroleum ether, toluene, xylene, ethyl benzene

The compounds of the invention according to formula (I) arecharacterised by low toxicity with a good anti-tumor effect.

The compound according to Example 1 has for example an EC₉₀ of 2.9 μg/mlin the L1210-cell culture experiment.

The EC₉₀ is the concentration of an anti-tumor substance in μg/ml whichinhibits the growth of cancer cells by 90% in vitro compared to acontrol experiment without addition of the anti-tumor substance.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate the invention.

EXAMPLE 1

IUPAC name

2- (Octadecyloxy)hydroxyphosphenyl!oxy!-As,As,As-trimethyl ethylarsonium inner salt ##STR9## 2.3 ml (25 mmol) Phosphorus oxychloride aredissolved in 15 ml chloroform and reacted at 0° C.-5° C. dropwise with asolution of 6.1 g (22.5 mmol) octadecanol in 25 ml chloroform containing8 ml pyridine. Duration of addition: 30 min to 1 hour. The mixture isstirred for a further hour at room temperature and 7.4 g (30 mmol)arsenocholine bromide z is then added thereto in one portion. 10 mlPyridine are added dropwise to this solution so that the temperaturedoes not exceed 20° C.-25° C. When addition is completed the mixture isstirred for a further 3 hours at room temperature, hydrolized aftercooling to 5° C. to 10° C. with 4 ml water and washed with, in eachcase, 20 ml water/methanol (1:1), 3 percent sodium carbonate/methanol(1:1), 3 percent citric acid/methanol (1:1) and finally water/methanol(1:1). The organic phase is dried over magnesium sulphate, concentratedand the residue taken up in 96 percent ethanol. After filtration themixture is stirred with 30 g ion exchanger Amberlite® MB 3. The resultis sucked off via kieselguhr/active charcoal, concentrated in a vacuumand allowed to crystallize under acetone.

Yield: 2.54 g (23%)

    ______________________________________    Elementary analysis:                 C           H       As    ______________________________________    calc.        55.64%      10.15%  15.09%    found        55.71%      10.41%  14.1%                 55.93%      10.58%    ______________________________________

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.53.

EXAMPLE 2

IUPAC name

2- (hexadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethyl ethylarsonium inner salt ##STR10##

Preparation of this compound is carried out by analogy with Example 1from 2.3 ml (25 mmol) phosphorous oxychloride, 5.5 g (22.5 mmol)hexadecanol, 8+10 ml pyridine and 7.4 g (30 mmol) arsenocholine bromide.Purification by treatment with 23 g ion exchanger Amberlite0 MB3 in 96percent ethanol.

Yield: 1.4 g (13%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             53.84%   9.90%    found             53.45%  10.16%                      53.67%  10.20%    ______________________________________

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.48.

EXAMPLE 3

IUPAC name

2- (cis-13-docosenyloxy)hydroxyphosphinyl!oxy-As,As,As-trimethyl ethylarsonium inner salt ##STR11##

Preparation is carried out by analogy with Example 1 from 2.3 ml (25mmol) phosphorous oxychloride, 7.3 g (22.5 mmol) erucyl alcohol, 8+10 mlpyridine and 7.4 g (30 mmol) arsenocholine bromide. Purification bytreatment with 23 g ion exchanger Amberlite® MB3 in 96 percent ethanol.

Yield: 1.1 g (10%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             55.28%  10.31%    found             54.98%  10.19%                      55.08%  10.30%    ______________________________________

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.52.

EXAMPLE 4

IUPAC name

2- (octadecyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethyl ethylphosphonium inner salt ##STR12##

Preparation was carried out by analogy with Example 1 from 4.6 ml (50mmol) phosphorous oxychloride, 12.2 g (45 mmol) octadecanol, 16+20 mlpyridine and 12.1 g (60 mmol) phosphocholine bromide. Purification wasby treatment with 50 g ion exchanger Amberlite® MD3 in 96 percentethanol.

Yield: 2.1 g (10%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             60.04%  11.14%    found             60.94%  11.53%                      60.44%  11.42%    ______________________________________

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.43.

EXAMPLE 5 2- (hexadecyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethyl ethylphosphonium inner salt ##STR13##

Preparation was carried out by analogy with Example 1 from 4.6 ml (50mmol) phosphorous oxychloride, 10.9 g (45 mmol) hexadecanol, 16+20 mlpyridine and 12.1 g (60 mmol) phosphocholine bromide. Purification bytreatment with ion exchanger Amberlite® MB3 in 96 percent ethanol.

Yield: 5.2 g (27%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             59.41%  10.92%    found             58.73%  11.16%                      59.19%  12.02%    ______________________________________

RF=0.47

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.43.

EXAMPLE 6 2- (Cis-13-docosenyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethylethyl phosphonium inner salt##STR14##

Preparation by analogy with Example 1 from 3.5 ml (38 mmol) phosphorousoxychloride, 11.2 g (34 mmol) erucyl alcohol, 12+15 ml pyridine and 9.2g (46 mmol) phosphocholine bromide. Purification by treatment with 45 gion exchanger Amberlite® MB3 in 96 percent ethanol.

Yield: 1.9 g (11%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             60.76%  11.14%    found             60.56%  11.35%                      61.39%  11.54%    ______________________________________

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10) RF=0.47.

EXAMPLE 7 2- (Octadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-triethylethyl arsonium inner salt ##STR15##

Preparation by analogy with Example 1 from 3.5 ml (38 mmol) phosphorousoxychloride, 9.33 g (35 mmol) octadecanol, 12+15 ml pyridine-and 13.2 g(46 mmol) (2-hydroxyethyl)-arsonium bromide. Purification by treatmentwith ion exchanger Amberlight® MB3 in 96 percent ethanol and subsequentcolumn chromatography on silica gel with CH₂ Cl₂ /CH₃ OH/25 percentammonia 70:40:10.

Yield: 3.39 g (18%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             54.35%  10.52%    found             54.65%  11.58%                      54.41%  11.78%    ______________________________________

R_(F) =0.60

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 8 2- (Hexadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-tri-ethylethyl arsonium inner salt ##STR16##

Preparation by analogy with Example 1 from 3.5 ml (38 mmol) phosphorousoxychloride 8.43 g (35 mmol) hexadecanol, 12+15 ml pyridine and 13.2 g(46 mmol) triethyl(2-hydroxyethyl) arsonium bromide. Purification bytreatment with ion exchanger Amberlite® MB3 in 96 percent ethanol andsubsequent column chromatography on silica gel with CH₂ Cl₂ /CH₃ OH/25percent ammonia 70:40:10.

Yield: 2.26 g (13%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             51.05%  10.35%    found             50.22%  11.37%                      50.81%  11.77%    ______________________________________

R_(F) =0.57

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 9 2-Cis-13-docosenyloxy)hydroxyphosphinyl!oxy!-As,As,As-triethylethylarsonium inner salt ##STR17##

Preparation by analogy with Example 1 from 3.5 ml (38 mmol) phosphorousoxychloride 11.4 g (35 mmol) erucyl alcohol, 12+15 ml pyridine and 13.2g (46 mmol) trimethyl(2-hydroxyethyl) arsonium bromide. Purification bytreatment with 30 g ion exchanger Amberlite® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with CH₂ Cl₂ /CH₃OH/25 percent ammonia 70:40:10.

Yield: 4.50 g (22%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             51.05%  10.35%    found             50.22%  11.37%                      50.81%  11.77%    ______________________________________

R_(F) =0.57

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 10 3- (Octadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylpropylarsonium inner salt ##STR18##

Preparation by analogy with Example 1 from 4.0 ml (38 mmol) phosphorousoxychloride 10.8 g (35 mmol) octadecanol, 14+17 ml pyridine and 13.2 g(53 mmol) trimethyl-3-hydroxypropyl arsonium bromide. Purification bytreatment with 30 g ion exchanger Amberlight® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with CH₂ CL₂ /CH₃OH/25 percent ammonia 70:40:10.

Yield: 1.97 g (10%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             52.74%  10.33%    found             52.22%  10.38%                      52.19%  10.37%    ______________________________________

R_(F) =0.47

Thin layer chromatogram:

(chloroform/methanol/25 percent ammonia 70:40:10).

EXAMPLE 11 3- (Hexadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylpropylarsonium inner salt ##STR19##

Preparation by analogy with Example 1 from 4.0 ml (43 mmol) phosphorousoxychloride 9.7 g (40 mmol) hexadecanol, 14+17 ml pyridine and 13.6 g(53 mmol) trimethyl(3-hydroxypropyl) arsonium bromide. Purification bytreatment with 30 g ion exchanger Amberlite® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with CH₂ Cl₂ /CH₃OH/25 percent ammonia 70:40:10.

Yield: 2.0 g (10%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             51.86%  10.09%    found             51.55%  10.05%                      51.74%  10.17%    ______________________________________

R_(F) =0.47

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia70:40:10).

EXAMPLE 12 3-(Cis-13-docosenyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylpropylarsonium inner salt ##STR20##

Preparation by analogy with Example 1 from 4.0 ml (43 mmol) phosphorousoxychloride 13.0 g (40 mmol) erucyl alcohol, 14+17 ml pyridine and 13.2g (53 mmol) trimethyl(3-hydroxypropyl) arsonium bromide. Purification bytreatment with 30 g ion exchanger Amberlite® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with CH₂ Cl₂ /CH₃OH/25 percent ammonia 70:40:10.

Yield: 2.4 g (11%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             54.36%  10.43%    found             54.45%  10.34%                      54.86%  10.51%    ______________________________________

R_(F) =0.50

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia70:40:10).

EXAMPLE 13 3-(Cis-13-docosenyloxy)hydroxyphosphinyl!oxy!-P,P,P-tri-methylpropylphosphonium inner salt ##STR21##

Preparation by analogy with Example 1 from 4.2 ml (45 mmol) phosphorousoxychloride 13.8 g (42 mmol) erucyl alcohol, 14+18 ml pyridine and 12.0g (56 mmol) trimethyl(3-hydroxypropyl) arsonium bromide. Purification bytreatment with 45 g ion exchanger Amberlite® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with CH₂ Cl₂ /CH₃OH/25 percent ammonia 70:40:10.

Yield: 2.93 g (13%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             59.44%  11.22%    found             59.28%  10.92%                      59.57%  11.54%    ______________________________________

R_(F) =0.25

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 14 3- (Octadecyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethylpropylphosphonium inner salt ##STR22##

Preparation by analogy with Example 1 from 4.2 ml (45 mmol) phosphorousoxychloride 11.4 g (42 mmol) octadecanol, 14+18 ml pyridine and 12.2 g(56 mmol) trimethyl (3-hydroxypropyl hydroxpropyl phosphonium bromide.Purification by treatment with 55 g ion exchanger Amberlite® MB3 in 96percent ethanol and subsequent column chromatography on silica gel withCH₂ Cl₂ /CH₃ OH/25 percent ammonia 70:40:10.

Yield: 2.27 g (11%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             58.39%  11.23%    found             59.08%  11.42%                      58.63%  11.39%    ______________________________________

R_(F) =0.50

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 15 3- (Hexadecyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethylpropylphosphonium inner salt ##STR23##

Preparation by analogy with Example 1 from 4.2 ml (45 mmol) phosphorousoxychloride 10.2 g (42 mmol) hexadecanol, 14+18 ml pyridine and 12.0 g(56 mmol) trimethyl(3-hydroxypropyl phosphonium bromide. Purification bytreatment with 55 g ion exchanger Amberlite® MB3 in 96 percent ethanoland subsequent column chromatography on silica gel with silica gel withCH₂ Cl₂ /CH₃ OH/25 percent ammonia 70:40:10.

Yield: 1.86 g (10%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             57.87%  11.04%    found             57.30%  11.20%    ______________________________________

R_(F) =0.50

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 16 3- (Nonadecyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethyl-ethylphosphonium inner salt ##STR24##

Preparation by analogy with Example 1 from 3.2 ml (35 mmol) phosphorousoxychloride 9.18 g (32 mmol) nonadecanol, 11+14 ml pyridine and 8.64 g(43 mmol) phosphocholine bromide. Purification by treatment with 25 gion exchanger Amberlite® MB3 in 96 percent ethanol and subsequentdecocting twice with acetone.

Yield: 1.85 g (12%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             60.61%  11.23%    found             60.69%  11.55%                      61.01%  11.39*    ______________________________________

R_(F) =0.58

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 17 3- (Eicosyloxy)hydroxyphosphinyl!oxy!-P,P,P-trimethylethylphosphonium inner salt ##STR25##

Preparation by analogy with Example 1 from 3.2 ml (35 mmol) phosphorousoxychloride 9.63 g (32 mmol) eicosanol, 11+14 ml pyridine and 8.64 g (43mmol) phosphocholine bromide. Purification by treatment with 25 g ionexchanger Amberlite® MB3 in 96 percent ethanol and subsequent decoctingtwice in acetone.

Yield: 0.02 g (7%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             61.32%  11.32%    found             61.72%  11.65%                      61.55%  11.47%    ______________________________________

R_(F) =0.53

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 18 2- (Nonadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethethylarsonium inner salt ##STR26##

Preparation by analogy with Example 1 from 4.6 ml (50 mmol) phosphorousoxychloride 12.8 g (45 mmol) nonadecanol, 16+20 ml pyridine and 14.7 g(60 mmol) arsenocholine bromide. Purification by treatment with 55 g ionexchanger Amberlite® MB3 in 96 percent ethanol.

Yield: 4.05 g (18%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             55.48%  10.28%    found             55.89%  10.43                      55.89   10.52%    ______________________________________

R_(F) =0.45

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 19 2- (Eicosyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylethylarsonium inner salt ##STR27##

Preparation by analogy with Example 1 from 4.6 ml (50 mmol) phosphorousoxychloride 13.4 g (45 mmol) eicosanol, 16+20 ml pyridine and 14.7 g (60mmol) arsenocholine bromide. Purification by treatment with 50 g ionexchanger Amberlite® MB3 in 96 percent ethanol.

Yield: 2.81 g (12%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             57.24%  10.38%    found             56.92%  10.52%                      57.02%  10.36%    ______________________________________

R_(F) =0.45

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 20 2-(Heptadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylethyl arsoniuminner salt ##STR28##

Preparation by analogy with Example 1 from 4.6 ml (50 mmol) phosphorousoxychloride 11.5 g (45 mmol) heptadecanol, 16+20 mol pyridine and 14.7 g(60 mmol) arsenocholine bromide. Purification by treatment with 35 g ionexchanger Amberlite® MB3 in 96 percent ethanol and subsequent stirringin acetone.

Yield: 1.20 g (6%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             52.79%  10.07%    found             52.46%  9.95%                      53.26%  10.30%    ______________________________________

R_(F) =0.45

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 21 2-(Octadecyloxy)hydroxyphosphinyl!oxy!-P,P-diethyl-P-phenyl-ethylphosphonium inner salt ##STR29##

Preparation by analogy with Example 1 from 2.3 ml (25 mmol) phosphorousoxychloride 7.17 g (26.5 mmol) canol, 8+10 ml pyridine and 7.28 g (26.5mmol) diethyl-(2-hydroxyethylJ-phenyl phosphonium bromide. Purificationby treatment with 21 g ion exchanger Amberlite® MB3 in 96 percentethanol and recrystallisation twice from acetone. Yield: 1.76 g (13%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             64.26%  10.43%    found             64.03%  10.77%                      64.24%  10.92%    ______________________________________

R_(F) =0.37

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5)

EXAMPLE 22 2- (Cis-13-docosenyloxy)hydroxyphosphinyl!oxy!-P,P-diethylP-phenyl-ethyl phosphonium inner salt ##STR30##

Preparation by analogy with Example 1 from 2.3 ml (25 mmol) phosphorousoxychloride 8.6 g (27 mmol) erucyl alcohol, 8+10 ml pyridine and 7.28 g(27 mmol) (2-hydroxyethyl)phenyl phosphonium bromide. Purification bytreatment with 30 g ion exchanger Amberlite® MB3 in 96 percent ethanoland crystallisation from acetone.

Yield: 2.53 g (17%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             65.46%  10.50%    found             65.71%  10.33%                      65.59%  10.99%    ______________________________________

R_(F) =0.37

Thin layer chromatogram: (chloroform/methanol/25 percent ammonia80:25:5).

EXAMPLE 23 2-(4'-Dodecylcyclohexyl)methyloxy)hydroxyphosphinyl!oxy!As,As,As-trimethylethylarsonium inner salt ##STR31##

Preparation by analogy with Example 1 from 2.4 ml (26 mmol) phosphorousoxychloride 6.50 g (23 mmol) dodecylcyclohexyl methanol, 9+12 mlpyridine and 7.59 g (31 mmol) arsenocholine bromide. Purification bytreatment with 30 g ion exchanger Amberlite® MB3 in 96 percent ethanoland stirring in acetone.

Yield: 1.64 g (14%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             56.68%  9.91%    found             56.66%  10.25%                      56.91%  10.28%    ______________________________________

R_(F) =0.37

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 24 1-0-Octadecyl-2-0-methyl-rac-glycerophosphoarsenocholine##STR32##

Preparation by analogy with Example 1 from 3.0 ml (33 mmol) phosphorousoxychloride 10.8 g (30 mmol) 1-0-Octadecyl-2-0-methyl-rac-glycerol 11+13ml pyridine and 9.8 g (40 mmol) arsenocholine bromide. Purification bytreatment with 55 g ion exchanger Amberlite® MB3 in 96 percent ethanoland stirring with acetone.

Yield: 5.83 g (33%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             55.47%  10.00%    found             55.23%  10.23%                      55.79%  10.26%    ______________________________________

R_(F) =0.57

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 25 1-0-Octadecyl-2-0-methyl-rac-glycerophosphophosphocholine##STR33##

preparation by analogy with Example 1 from 4.6 ml (50 mmol) phosphorousoxychloride 16.1 g (45 mmol) 1-0-Octadecyl-2-0-methyl-rac-glycerol 16+20ml pyridine and 12.1 g (60 mmol) phosphocholine bromide. Purification bytreatment with 45 g ion exchanger Amberlite® MB3 in 96 percent ethanoland stirring with acetone.

Yield: 6.25 g (26%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             58.99%  10.82%    found             58.73%  11.19%                      59.12%  11.05%    ______________________________________

R_(F) =0.52

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 26 2-Octadecyloxy)hydroxyphosphinyl!oxy!-Sb,Sb,Sb-trimethylethyl stiboniuminner salt ##STR34##

Preparation by analogy with Example 1 from 2.1 ml (23 mmol) phosphorousoxychloride 6.49 g (24.5 mmol) octadecanol, 7+9 ml pyridine and 7.0 g(24 mmol) stibonocholine bromide. Purification by treatment with 15 gion exchangerx Amberlite® MB3 and subsequent column chromatography onsilica gel with CH₂ Cl₂ /CH₃ OH/25 percent ammonia 80:25:5. Theproduct-containing fractions are extracted with diethylether andconcentrated.

Yield: 1.0 g (8%)

    ______________________________________    Elementary analysis:                      C       H    ______________________________________    calc.             47.68%  9.39%    found             47.54%  9.45%                      47.58%  9.28%    ______________________________________

R_(F) =0.62

Thin layer chromatogram: (chloroform/methanol/1 M sodium acetate in 25percent ammonia 70:40:10).

EXAMPLE 27

Tests with KB cells were carried out as a Soft-Agar-Colony-Assay inaccordance with Salmon and Hamburger, N. Engl. J. Med. 298, 132 (1987).Set forth in Table 1 is the respective concentration of the testsubstance which inhibits the formation of the colony up to 90% (EC₉₀)compared to the reference. The effective criteria determined was EC₉₀<10 μg/ml.

The substances were administered orally in solution with the help of anesophagus probe (respective dosages in parenthesis).

Indicated is the growth inhibition index (Wachstumshemmungsindex WHI) inpercent which was reached and which can be calculated as follows:##EQU1## with W_(C) =median tumor weight difference in the referencegroup based on day 0

W_(t) =corresponding value for the treated group

Values exceeding 100 indicate tumor regressions in relation to thestarting size of the tumor. Value 100 means that the tumors had notchanged in size by the end of the therapy compared to the beginning ofthe tests (but were clearly smaller than the tumors of the referenceanimals). Values ranging between 0 and 100 indicate an inhibition of thetumor growth compared to the references. Values below 0 indicate thatthe tumor growth was stimulated. KB in vivo represents a tumor model inwhich KB cells are transplanted subcutaneously into naked NMRI mice.DMBA in vivo represents a tumor model in which tumors of the milkinguinal were induced chemically in female test rats by administeringDimethylbenzanthracen (DMBA). EC₉₀ values which exceed 10 are consideredineffective.

The type of the composition of the agent as well as how much and overwhat period of time it is to be applied, are those conventionallyemployed in the literature.

                  TABLE 1    ______________________________________    Exam-          EC.sub.90   μg/ml!    ple            (KB cells WHI  %!   WHI  %!    No.   D-Number in vitro) (KB in vivo)                                       (DMBA in vivo)    ______________________________________    1     D-21805  3.2       42.9      112.8                             (1 × 511 mg/kg)                                       (4 × 100 mg/kg)    2     D-21819  27        not prep. not prep.    3     D-21820  >10       not prep. not prep.    4     D-21940  3.1       111       108.7                             (2 × 316 mg/kg)                                       (4 × 147 mg/kg)    5     D-21949  >10       not prep. not prep.    6     D-21941  >10       not prep. 43.9                                       (4 × 147 mg/kg)    7     D-22276  3.0       not prep. not prep.    8     D-22277  >10       not prep. not prep.    9     D-22278  >10       not prep. not prep.    10    D-22285  5.8       104       not prep.                             (2 × 316 mg/kg)    11    D-22286  >10       not prep. not prep.    12    D-22287  >10       not prep. not prep.    13    D-22288  >10       not prep. not prep.    14    D-22348  3.0       not prep. not prep.    15    D-22349  >10       not prep. not prep.    16    D-22350  2.6       not prep. not prep.    17    D-22351  3.0       not prep. not prep.    18    D-22352  3.0       not prep. not prep.    19    D-22353  insoluble not prep. not prep.    20    D-22423  3.2       not prep. not prep.    21    D-22566  3.1       not prep. not prep.    22    D-22567  3.1       not prep. not prep.    23    D-22616  >10       not prep. not prep.    24    D-22651  2.8       not prep. 73                                       (4 × 100 mg/kg)    25    D-22652  2.7       not prep. not prep.    ______________________________________

EXAMPLE 28

Tests measuring the inhibiting effect on Leishmania mexicana(promastigotes) were conducted in accordance with the procedures setforth in R. F. Stieger et al., European Journal of Biochemistry, Vol.105(1980), pp.163-175 and D. T. Hardt, and F. R. Opperdoes, Molecular andBiochemical Parasitology Vol. 113 (1984), pp. 159-172.

                  TABLE 2    ______________________________________    Inhibiting effect on Leishmania mexicana (promastigotes),    indicated as EC.sub.90  values (partially mean values of two values)    Substance EC.sub.90   μg/ml!                          Range   EC.sub.90   μmol/ml!    ______________________________________    Pentosam  1,000.0    (standard)    Example 1 0.8                 1.8    Example 4 0.8         0.1     1.8 ± 0.22    Example 24              0.9                 1.5    Example 25              1.8         0.2     3.3 ± 0.37    ______________________________________

What is claimed is:
 1. A method for the treatment of a solid tumordisease comprising administering to a person suffering therefrom aninhibitory amount of a compound having the following formula, ##STR35##wherein: R⁵ is a straight chain or branched alkyl group having 10-24carbon atoms which may also contain one to three double and/or triplebonds;A is either a single bond or is a moiety selected from the groupconsisting of: ##STR36## where R⁷ is a straight chain alkyl group having1 to 4 carbon atoms, with the proviso that when A is a single bond, X isoxygen, sulfur or imine and that when A is any one of formula (II) to(VI), X is oxygen or sulfur, with the further proviso that when A is anyone of formula (II) to (VI), A is bound to the phosphorous of formulavia the oxygen atom of any one of formula (II) through (VI); A₁ is astraight-chain or branched alkyl radical having 2 to 10 carbon atoms; R⁶is .sup.(+) YR⁸ R⁹ R¹⁰ or has formula VII: ##STR37## where Y is selectedfrom the group consisting of P, As, Sb, and Bi and when R⁶ is .sup.(+)YR⁸ R⁹ R¹⁰, R⁸ -R¹⁰ may all be the same or different and are selectedfrom the group consisting of hydrogen, straight chain alkyl groupshaving 1 to 6 carbon atoms and cyclic alkyl groups having 3 to 6 carbonatoms, and when R⁶ is a substituent having formula VII, then R⁸ and Yare defined as above, and n is 0 or 1, and W is selected from the groupconsisting of methylene, oxygen, imine and sulfur, with the proviso thatwhen n=0, W is methylene when Y is P, As or Sb.
 2. A method according toclaim 1 wherein the solid tumors are selected from the group consistingof mamma carcinoma, head-neck carcinoma, colon carcinoma and prostatecarcinoma.
 3. The method according to claim 1 wherein the inhibitoryamount is a dosage between 5-100 mg/kg body weight.
 4. The methodaccording to claim 1 wherein the inhibitory amount is a dosage between100-500 mg/kg body weight.
 5. A method according to claim 1 wherein thecompound is 2-(octadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylethyl arsoniuminner salt.
 6. The compound 2-(octadecyloxy)hydroxyphosphinyl!oxy!-As,As,As-trimethylethyl arsoniuminner salt.